1. Field of the Invention
The present invention relates to a novel process for the preparation of hydroxyphosphonylmethoxypropyl nucleosides, and novel intermediates produced therein.
2. Background Art
Nucleoside analogs possessing a 3-hydroxy-2-(phosphonylmethoxy)propyl (HPMP) side chain have been reported as potent antiviral compounds having a broad spectrum of activity. Examples of compounds belonging to this class include HPMP-adenine (HPMPA), HPMP-guanine (HPMPG) and HPMP-cytosine (HPMPC). HPMP-substituted nucleosides contain a chiral center and it has been postulated that the biological activity may reside in one enantiomer and not the other. It is therefore desirable to develop a synthetic method which will preferentially yield the active enantiomer using readily available and inexpensive starting materials.
Bronson et al (J. Med. Chem., 1989, 32:1457) reported the synthesis of (S)-HPMPC which involves the coupling of cytosine with 3-O-benzyl-2-O-[(diethylphosphonyl)methyl]-3-O-(methylsulfonyl)glycerol, followed by subsequent deprotection to afford the product. The glycerol starting material is derived from chiral (R)-glycerol acetonide.
Holy et al (Coll. Czech. Chem..Comm., 1989, 54:2470) reported the synthesis of (S)-HPMPC by reacting (R)-glycerol acetonide tosylate with 4-methoxy-2-pyrimidinone, the resultant product is then converted to 1-[(2,3-dihydroxy)propyl]cytosine. The latter compound is reacted with chloromethylphosphonyl dichloride, and the product is converted to (S)-HPMPC by base catalyzed rearrangement.
Glycerol acetonide was also used in the synthesis of (S)-HPMPA (Webb, Nucleosides and Nucleotides, 1989, 8:619) and HPMPG (Terry et al, Antiviral Res., 1988, 10:235). These procedures all require the use of the expensive chiral glycerol acetonide as starting material, and involve multi-step process requiring chromatographic purifications of intermediate compounds.
The reaction of glycidol with adenine, cytosine or uracil to form the 2,3-dihyroxypropyl substituted nucleosides was reported by Ueda et al, J. Heterocyclic Chem., 1971, 8:827. The reaction of (.+-.)- glycidol with thymine or 5-fluorouracil was reported by Seiter et al, Bull. Chem. Soc. Jpn., 1973, 46:1572. The prior art does not disclose or suggest the process of the present invention for the preparation of HPMP-nucleotides which offers marked improvement over previously known methods.